Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility.

Abstract

The cellular and molecular basis of sex-dimorphic autoimmune diseases, such as the CNS demyelinating disease multiple sclerosis (MS), remains unclear. Our studies in the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE), reveal that sex-determined differences in <i>Il33</i> expression by innate immune cells in response to myelin peptide immunization regulate EAE susceptibility. IL-33 is selectively induced in PLP_139-151-immunized males and activates type 2 innate lymphoid cells (ILC2s), cells that promote and sustain a nonpathogenic Th2 myelin-specific response. Without this attenuating IL-33 response, females generate an encephalitogenic Th17-dominant response, which can be reversed by IL-33 treatment. Mast cells are one source of IL-33 and we provide evidence that testosterone directly induces <i>Il33</i> gene expression and also exerts effects on the potential for <i>Il33</i> gene expression during mast cell development. Thus, in contrast to their pathogenic role in allergy, we propose a sex-specific role for both mast cells and ILC2s as attenuators of the pathogenic Th response in CNS inflammatory disease.